Anti-Markovnikov hydroamination and hydrothiolation of electron-deficient vinylarenes catalyzed by well-defined monomeric copper(I) amido and thiolate complexes

Article abstract of DOI:10.1039/b715507g

Monomeric Cu(I) amido and thiolate complexes that are supported by the N-heterocyclic carbene ligand 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene (IPr) catalyze the hydroamination and hydrothiolation of electron-deficient vinylarenes with reactivity patterns that are consistent with an intermolecular nucleophilic addition of the amido/thiolate ligand of (IPr)Cu(XR) (X = NH or S; R = Ph, CH₂Ph) to free vinylarene. The Royal Society of Chemistry.

Full text of DOI:10.1039/b715507g

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Anti-Markovnikov hydroamination and hydrothiolation of electron-
deficient vinylarenes catalyzed by well-defined monomeric copper(I)
amido and thiolate complexes{
Colleen Munro-Leighton, Samuel A. Delp, Nikki M. Alsop, Elizabeth D. Blue and T. Brent Gunnoe*
Received (in Berkeley, CA, USA) 8th October 2007, Accepted 11th October 2007
First published as an Advance Article on the web 24th October 2007
DOI: 10.1039/b715507g
A benzene solution of 5 mol% (based on olefin) (IPr)Cu(NHPh)
(1) with aniline and para-nitrostyrene produces the ‘‘anti-
Markovnikov’’ product N-phenyl-para-nitrophenethylamine in
77% yield after 21 h at 80 uC (eqn 1). All yields given in eqn 1–5
have been determined by 1H NMR spectroscopy against an
internal standard. All organic products have been isolated and
fully characterized, and isolated yields are provided in the ESI.{ As
previously discussed by Hartwig et al., the use of excess amine is
required to produce substantial or complete conversion.7 Control
reactions in the absence of Cu catalyst do not result in
hydroamination of vinylarene.
Monomeric Cu(I) amido and thiolate complexes that are
supported by the N-heterocyclic carbene ligand 1,3-bis(2,6-
diisopropylphenyl)imidazol-2-ylidene (IPr) catalyze the hydro-
amination and hydrothiolation of electron-deficient vinylarenes
with reactivity patterns that are consistent with an intermole-
cular nucleophilic addition of the amido/thiolate ligand of
(IPr)Cu(XR) (X = NH or S; R = Ph, CH2Ph) to free
vinylarene.
The formation of C–S and C–N bonds via the addition of S–H/N–
H bonds of thiols/amines across olefins is a promising atom
efficient synthetic method.1 Only a few transition metal catalysts
for the regioselective hydroamination of styrenes have been
reported.2 Rarely observed ‘‘anti-Markovnikov’’ selectivity has
been reported with Rh and Ru systems,2e–h while metal halides in
combination with triflate salts or metal triflate systems catalyze
‘‘Markovnikov’’ addition of arylsulfonamides to vinylarenes and
other olefins.3 It is likely that many of these metal halide or triflate
systems generate protic acid that functions as the active catalyst.4
Similar to hydroamination, examples of transition metal catalyzed
hydrothiolation of vinylarenes are relatively rare.5
We have recently prepared a series of monomeric CuI complexes
with formally anionic heteroatomic ligands including amido,
alkoxo, aryloxo and thiolate fragments.6 Herein, we report that
(IPr)Cu(X) {X = NHR or SR; IPr = 1,3-bis(2,6-diisopropylphe-
nyl)imidazol-2-ylidene, Chart 1} systems catalyze regioselective
‘‘anti-Markovnikov’’ hydroamination and hydrothiolation of
activated vinylarenes.
ð1Þ
The reaction of aniline and para-cyanostyrene is also catalyzed
by 1, but a higher temperature (120 uC) and longer reaction time
are required (eqn 1). Attempts at the catalytic hydroamination
with aniline for vinylarenes that possess para-substituents with
reduced electron-withdrawing ability do not yield new organic
products. For example, heating solutions of 1 (C6D6) and aniline
with para-X-styrene {where X = CF3 (sp2 = 0.65), Br (sp2 = 0.25),
2
2
Cl (sp = 0.19), or H (sp = 0)} to 120 uC results in no change
2
after 48 h (sp for NO2 = 1.27 and CN = 1.00).
Although we have not been able to isolate the CuI amido
complex formed from benzylamine, (IPr)Cu(NHCH2Ph) (2), this
system can likely be generated in situ upon reaction of
(IPr)Cu(NHPh) and benzylamine. The combination of 1 and
benzylamine at 100 uC produces a new (IPr)Cu system and free
aniline. Attempted isolation of 2 results in decomposition (see the
ESI{). Use of 1 as catalyst precursor with benzylamine extends
the range of substituted styrenes that undergo hydroamination to
the p-CF3 compound (eqn 2). Thus, the transformations
with benzylamine are successful when the para substituent of
the vinylarene is nitro, cyano or perfluoromethyl (eqn 2),
while the analogous reaction of the p-CF3–styrene with aniline
does not undergo reaction after 7 days (120 uC). Apparently,
complex 1 is not sufficiently reactive to enter the catalytic
cycle for the less activated perfluoromethyl styrene, and we
presume that catalysis with the p-CF3–styrene and benzylamine
occurs via initial formation of complex 2. For catalysis
Chart 1 (IPr)Cu(X) [X = NHPh (1), NHCH2Ph (2), SPh (3) or
SCH2Ph (4)] catalyst precursors.
Department of Chemistry, North Carolina State University, Raleigh,
27695-8204, USA. E-mail: brent_gunnoe@ncsu.edu;
Fax: +1 919-515-8909; Tel: +1 919-513-3704
{ Electronic supplementary information (ESI) available: Details of
synthetic procedures, characterization of organic compounds and
complete tables of catalytic results. See DOI: 10.1039/b715507g
1
with benzylamine, yields by H NMR are quantitative for X =
CN or CF3.
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Chem. Commun., 2008, 111–113 | 111

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catalytic conversion of aniline and p-NO2–styrene is successful,
attempted catalysis with aniline and m-NO2–styrene fails to yield
hydroamination at temperatures up to 100 uC after 24 h (eqn 3).
ð2Þ
ð3Þ
In addition to control reactions in the absence of Cu amido
complexes, which do not give the hydroamination product (see
above), we attempted to catalyze these reactions with lithium
amido or pyridine as base. Under conditions identical to the Cu-
catalyzed reactions shown in eqn 1, aniline/para-nitrostyrene and
aniline/para-cyanostyrene do not react in the presence of 5 mol%
[Li][NHPh]. Likewise, attempted reaction (again, under conditions
analogous to the Cu-catalyzed reactions) of benzylamine with
para-cyanostyrene and aniline with para-nitrostyrene in the
presence of pyridine do not give the hydroamination product.
Several mechanisms have been elucidated for transition metal
catalyzed hydroamination (and related reactions) of olefins. For
example, early transition metal imido complexes have been
proposed to undergo initial net [2 + 2] cycloaddition of olefins.8
Hydroamination of olefins by late transition metal systems have
been proposed to occur by olefin coordination and subsequent
nucleophilic addition of the amine,1a formation of a p–arene
complex and activation toward nucleophilic addition of the
amine,2h olefin insertion into M–NR2 bonds,1a and formation of
g3-allyl complexes (for styrenes) followed by amine addition to the
allyl ligand.2a,c
As an additional confirmation of the importance of the
nucleophile, we attempted hydrothiolation of para-nitrostyrene
with (IPr)Cu(SR)/thiols, which are presumably more nucleophilic
than the (IPr)Cu(NHR)/amine analogs. Similar to the hydro-
amination reactions, using (IPr)Cu(SR) {R = Ph (3) or CH2Ph
(4)} as catalyst affords the hydrothiolation of the activated p-NO2
compound at room temperature (eqn 4). Under these conditions
(i.e., ,80 uC), reactions with less electron-withdrawing groups
(e.g., X = CN, CF3, Br, Cl or H) do not proceed to products.
ð4Þ
In an effort to demonstrate the potential utility of these Cu
catalysts, we have prepared N-methyl-N-benzyl-para-nitrophe-
nethylamine as shown in eqn 5. This compound is a precursor
to a class III antiarrhythmic agent and has been prepared in four
steps (overall yield 77%) from commercially available reagents in
reaction sequences that incorporate HBr, HCl, benzene, ethanol,
MeI, acetonitrile, benzaldehyde, potassium borohydride, formal-
dehyde and formic acid.9 Using (IPr)Cu(NHPh) as catalyst, we
have synthesized and isolated the amine in a single step from
commercially available reagents (eqn 5). By 1H NMR, the reaction
proceeds to y70% yield, and the amine has been isolated in y50%
yield. Although our unoptimized yield is lower than the previous
process, the procedure is simpler and generates fewer byproducts
and waste.
The hydroamination reactions catalyzed by complexes 1 and 2
appear to be dependent upon the electron withdrawing ability of
the para-substituent of the vinylarene. For the closely related
addition of aniline to acrylonitrile, we have reported evidence
supporting a pathway that involves rate-determining nucleophilic
addition of the amido ligand of (IPr)Cu(NHPh) to free
acrylonitrile.6c Similarly, we suggest that a related mechanism
may be operative for the hydroamination of vinylarenes in which
the rate-determining step is intermolecular nucleophilic addition of
the heteroatom to free vinylarene (Scheme 1). Although the data
are limited, the relative predilection toward hydroamination of
vinylarenes as a function of the para-substituent (i.e., reactivity
observed only for more electron-withdrawing groups) is consistent
with the proposed pathway. In addition, the more nucleophilic
benzylamine reacts with the p-NO2 and p-CN vinylarenes at lower
temperature than does aniline, and benzylamine reacts with the
p-CF3 while aniline does not (eqn 1–2). Furthermore, although
ð5Þ
In summary, we have reported well-defined monomeric Cu(I)
amido and thiolate complexes that catalyze the addition of N–H
and S–H bonds of amines and thiols to activated vinylarenes. The
anti-Markovnikov selectivity, which has only rarely been achieved
with transition metal catalysts, is consistent with a mechanism that
involves intermolecular X–C (X = N or S) bond formation and is
inconsistent with transformations catalyzed by Brønsted acid
impurities. Although non-catalyzed additions of amines to
activated vinylarenes in polar solvents have been reported,10 such
transformations were not accessible with aniline or alkyl anilines,
nor have they been reported for activating groups other than nitro.
The Cu-catalyzed reactions likely resemble simple base-catalyzed
olefin hydroamination,1f while potentially offering the flexibility of
transition metal catalysis [via adjustment of ligand(s) and metal
oxidation state] and milder reaction conditions (most base-
catalyzed hydroamination reactions of vinylarenes occur at higher
Scheme 1 Proposed mechanism for hydroamination and hydrothiola-
tion of vinylarenes [X = NHPh (1), NHCH2Ph (2), SPh (3) or SCH2Ph (4);
Y = electron withdrawing group].
112 | Chem. Commun., 2008, 111–113
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temperatures, often .150 uC).1f To our knowledge, reports of
transition metal catalyzed ‘‘anti-Markovnikov’’ hydroamination of
styrenes are limited to Ru and Rh, which are relatively expensive
metals. Even though more active catalysts will be required for
general synthetic utility, the development of Cu catalysts that are
active for the hydroamination of activated vinyl arenes is a first
step toward relatively inexpensive metals.
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We acknowledge the NSF (CAREER Award, CHE 0238167)
and the Alfred P. Sloan Foundation for financial support.
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